Bipolar disorders and headaches, such as migraines, and pain, including neuropathic pain, are varied maladies that on its face, are diverse.
A migraine headache is defined as a periodically occurring vascular headache characterized by pain in the head (usually unilateral), nausea, and vomiting, photophobia, phenophobia, vertigo and general weakness. Migraine is the most common type of vascular headache and affects as many as 15% of the world's population. Of the different types of migraines, classical migraine and common migraine are the two most prevalent. The major difference between the two types of migraines is that classical migraines are preceded by the appearance of neurological symptoms before an attack whereas common migraines are not preceded by such symptoms. Migraine is caused by intermittent brain dysfunction. However, the precise pathophysiological mechanisms involved are not understood. The head-pain is believed to involve blood vessel dilation and a reduction in the brain's pain relieving chemicals.
Neuropathic pain, on the other hand, can be described as pain associated with damage or permanent alteration of the central nervous system. Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia.
It results from injury to a nerve. In contrast to the immediate pain caused by tissue injury, neuropathic pain can develop days or months after a traumatic injury. Furthermore, while pain caused by tissue injury is usually limited in duration to the period of tissue repair, neuropathic pain frequently is long lasting or chronic.
Moreover, neuropathic pain can occur spontaneously or as a result of stimulation that normally is not painful.
The clinical causes of neuropathic pain are widespread and include both trauma and disease. For example, traumatic nerve compression, or crush, and traumatic injury to the brain or spinal cord are common causes of neuropathic pain. Furthermore, most traumatic nerve injuries also cause the formation of neuromas, in which pain occurs as a result of aberrant nerve regeneration. In addition, cancer-related neuropathic pain is caused when tumor growth painfully compresses adjacent nerves, the brain or the spinal cord. Neuropathic pain is associated with diseases such as diabetes or alcoholism.
Bipolar disorder is a neuropsychiatric disorder. Also known as bipolar affective disorder (BAD) or manic-depressive illness, it is characterized by episodes of elevated mood (mania) and depression. The most severe and clinically distinctive forms of BAD are BP-I (severe bipolar affective (mood) disorder), which affects 2-3 million people in the U.S. and SAD-M (schizoaffective disorder manic type). They are characterized by at least one full episode of mania, with or without episodes of major depression (defined by lower mood or depression, with associated disturbances in rhythmic behaviors, such as sleeping, eating and sexual activity).
The therapies are varied. Analgesics are often used to treat infrequent and mild migraines. Analgesics reduce the pain of a migraine and in the case of aspirin also discourage clumping of blood platelets. However, for moderate to severe migraines, stronger medication is necessary, e.g., ergotamine or 5-H-T1 agonists, like sumatriptan.
On the other hand, for neuropathic pain, opioid compounds (opiates) such as morphine may be utilized to treat the malady. Although effective as an analgesic, it is not always effective in treating neuropathic pain and may induce tolerance in patients. When a subject is tolerant to opioid narcotics, increased doses are required to achieve a satisfactory analgesic effect. At high doses, these compounds produce side effects, such as respiratory depression, which can be life threatening. In addition, opioids frequently produce physical dependence in patients, which may be related to the dose of opioid taken and the period of time over which it is taken by the subject.
But neuropathic pain and bipolar disorder frequently are resistant to available drug therapies. In addition, current therapies have serious side-effects including, for example, cognitive changes, sedation, nausea, and in the case of narcotic drugs addictions. Many patients suffering from neuropathic pain are elderly or have other medical conditions that particularly limit their tolerance of the side-effects associated with available drug therapy.
The inadequacy of current therapy in relieving neuropathic pain and bipolar disorders without producing intolerable side-effects frequently is manifested in the depression and suicidal tendency of chronic pain sufferers. Moreover, the present drugs are not effective for completely alleviating the pain from those who have moderate to heavy migraine headaches.
U.S. Pat. No. 5,885,999 discloses compounds which are useful for treating various maladies such as pain and headaches including migraines. These compounds are serine derivatives of the formula:
wherein m is zero, 1 or 2; and n is zero or 1, with the proviso that the sum total of m+n is 1 or 2;
R1 represents phenyl; naphthyl; benzohydryl; or benzyl, where the naphthyl group or any phenyl moiety may be substituted;
R2 represents hydrogen; phenyl; heteroaryl selected from indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; naphthyl; benzohydryl; or benzyl; wherein each heteroaryl, napthyl group and any phenyl moiety may be substituted;
R3 and R4 each independently represents hydrogen or C1-6alkyl or R3 and R4 together are linked so as to form a C1-3alkylene chain;
Q represents CR5R6 or NR5;
X and Y each independently represents hydrogen, or together form a group =0; and
Z represents a bond O, S, SO, SO2, NRc or —(CRcRd)-m where Rc and Rd each independently represent hydrogen or C1-6alkyl;
or a pharmaceutically acceptable salt thereof.
The compounds are alleged to be also useful in the treatment or prevention of inflammation, emesis and postherapeutic neuralgia.
In U.S. Pat. No. 6,228,825 to Tsai, et al., other amino acids and derivatives thereof are alleged to be useful for treating neuropsychiatric disorders, such as schizophrenia, Alzheimer's Disease, depression, autism, closed head injury, benign forgetfulness, childhood learning disorders, and attention deficit disorders. These drugs include (i) D-alanine or modified form thereof, provided that the composition is substantially free of D-cycloserine and/or (ii) serine (or a modified from thereof), and/or (iii) 105 to 500 mg of D-cycloserine (or a modified form thereof); and/or (iv) N-methylglycine (or a modified form thereof).
D-cycloserine, D-serine esters, D-serine or salts thereof have been disclosed to be useful in treating spinocerebellar degeneration. See, EP Application No. 1,084,704.
Peptides have also been alleged to be useful for treatment of pain and neurosis. More specifically, EPO application 997,147 discloses compounds of the formula:
    wherein R1 is
1) C1-15 alkyl,
2) C1-8 alkoxy,
3) phenyl,
4) C3-8 cycloalkyl,
5) hetero ring,
6) C1-4 alkyl substituted by phenyl, C3-8 cycloalkyl, or hetero ring,
7) C1-4 alkoxy substituted by phenyl, C3-8 cycloalkyl, or hetero ring, or
8) C2-4 alkenyl substituted by phenyl, C3-8 cycloalkyl, or hetero ring (with proviso that, all phenyl, C3-8 cycloalkyl and hetero ring in R1 group may be substituted by 1-3 substituent selected from the following (i)-(xi):                (i) C1-4 alkyl,        (ii) C1-4 alkoxy,        (iii) phenyl,        (iv) phenoxy,        (v) benzyloxy,        (vi) —SR5 (in which R5 is hydrogen or C1-4 alkyl),        (vii) C2-5 acyl,        (viii) halogen,        (ix) C1-4 alkoxycarbonyl,        (x) nitro,        (xi) —NR6R7 (in which R6 and R7 each independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R6 and R7 taken together with the nitrogen atom to which they are attached may represent 5-7 membered saturated hetero ring containing another one nitrogen atom or one oxygen atom));        
A is a bond, —CO— or —SO2—;
R2 is hydrogen or C1-4 alkyl optionally substituted by one phenyl;
D is C1-4 alkylene or C2-4 alkenylene;
E is                1) —COO—,        2) —OCO—,        3)—CONR8 (in which R8 is hydrogen or C1-4 alkyl),        4) —NR9CO— (in which R9 is hydrogen or C1-4 alkyl),        5) —O—,        6) —S—,        7) —SO—,        8) —SO2—,        9) —NR10— (in which R10 is hydrogen or C1-4 alkyl),        10) —CO—,        11) —SO2NR11— (in which R11 is hydrogen or C1-4 alkyl) or        12) —NR12SO2— (in which R12 is hydrogen or C1-4 alkyl);            R3 is
1) carbocyclic ring,
2) hetero ring, or
3) C1-4 alkyl substituted by carbocyclic ring or hetero ring (with proviso that, all carbocyclic ring and hetero ring in R3 may be substituted by 1-3 substituents selected from the following (i)-(xi);                (i) C1-4 alkyl,        (ii) C1-4 alkoxy,        (iii) phenyl,        (iv) phenoxy,        (v) benzyloxy,        (vi) —SR13 (in which R13 is hydrogen or C1-4 alkyl),        (vii) C2-5 acyl,        (viii) halogen,        (ix) C1-4 alkoxycarbonyl,        (x) nitro,        (xi) —NR14R15 (in which R14 and R15, each independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R14 and R15 taken together with the nitrogen atom to which they are attached may represent 5-7 membered saturated hetero ring containing another one nitrogen atom or one oxygen atom);            J is —O— or —NR16— (in which R16 is hydrogen or C1-4 alkyl);    R4 is
1) C1-8 alkyl,
2) carbocyclic ring,
3) hetero ring,
4) C1-8 alkyl substituted by 1-3 of substituent selected from the following (i)-(v);                (i) carbocyclic ring,        (ii) hetero ring,        (iii) COOR17 (in which R17 is hydrogen or C1-4 alkyl substituted by one phenyl (in which phenyl may be substituted by C1-4 alkoxy),        (iv) SR18 (in which R18 is hydrogen or C1-4 alkyl),        (v) OR19 (in which R19 is hydrogen or C14 alkyl), or            when J represents —NR16— group, R4 and R16 taken together with the nitrogen atom to which they are attached may represent hetero ring (with proviso that, all carbocyclic ring and hetero ring, and hetero ring represented by R4 and R16 taken together with the nitrogen atom to which they are attached may be substituted by 1-3 of substituent selected from the following (i)-(xi);            (i) C1-4 alkyl,        (ii) C1-4 alkoxy,        (iii) phenyl,        (iv) phenoxy,        (v) benzyloxy,        (vi) —SR20 (in which R20 is hydrogen or C1-4 alkyl),        (vii) C2-5 acyl,        (viii) halogen,        (ix) C1-4 alkoxycarbonyl,        (x) nitro,        (xi) —NR21R22 (in which R21 and R22 each independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R21 and R22 taken together with the nitrogen atom to which they are attached may represent 5-7 membered saturated hetero ring containing another one nitrogen atom or one oxygen atom), non-toxic salt thereof, or a hydrate thereof.        
Other peptides are known to exhibit central nervous system (CNS) activity and are useful in the treatment of epilepsy and other CNS disorders. These peptides, which are described in U.S. Pat. No. 5,378,729, to Kohn, et al., have the formula:
wherein
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group;
R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; and
R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z—Y wherein R2 and R3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group;
Z is O, S, S(O)a, NR4, PR4 or a chemical bond;
Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo; Z is a chemical bond, or
ZY taken together is NR4NR5R7, NR4OR5, ONR4R7, OPR4R5, PR4OR5, SNR4R7, NR4SR7, SPR4R5 or PR4SR7, NR4PR5R6 or PR4NR5R7,

R4, R5 and R6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R4, R5 and R6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and
R7 is R6 or COOR8, or COR8;
R8 is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and
n is 1-4; and
a is 1-3.
U.S. Pat. No. 5,773,475, the contents of which are incorporated by reference, also discloses additional compounds useful for treating CNS disorders. These compounds are N-benzyl-2-amino-3-methoxy-propionamides having the formula:
wherein
Ar is aryl which is unsubstituted or substituted with halo;
Q is lower alkoxy; and
Q1 is CH3.
Harris in U.S. Pat. No. 6,133,261 describes a method of treating or preventing stroke in a human by administering thereto an effective amount of a compound of the formula:R—NH—[—C(=Q)—C(R2)(R3)—NH—]n—C(=A)R1,wherein
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl (lower alkyl), heterocyclic, heterocyclic (lower alkyl), (lower alkyl) heterocyclic, lower cycloalkyl, lower cycloalkyl (lower alkyl), and R is unsubstituted or is substituted with at least one electron withdrawing group, or electron donating group;
R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl (lower alkyl), aryl, heterocyclic, (lower alkyl) heterocyclic, heterocyclic (lower alkyl), lower cycloalkyl, lower cycloalkyl (lower alkyl), each unsubstituted or substituted with an electron donating group or an electron withdrawing group and
R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl (lower alkyl), aryl, heterocyclic, heterocyclic (lower alkyl), (lower alkyl) heterocyclic, lower cycloalkyl, lower cycloalkyl (lower alkyl), SO3−, or Z—Y where R2 and R3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group;
Z is O, S, S(O)a, NR4, PR4, or a chemical bond;
Y is hydrogen, lower alkyl, aryl, aryl(lower alkyl), lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic (lower alkyl), (lower alkyl)heterocyclic, cycloalkyl, cycloalkyl (lower alkyl) and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo, Z is a chemical bond;
or ZY taken together is NR4NR5R7, NR4OR5, ONR4R7, OPR4R5, PR4OR5, SNR4R7, NR4SR7, SPR4R5, PR4SR7, NR4PR5R6, PR4NR5R7, NR4C(O)R5, SC(O)R5, NR4CO2R5, SCO2R5, NR4C(O)R5R6, NR4C(O)NR5S(O)aR6, NR4C(S)R5R6, NR4C(=Q)MNR5C(=A)OR6, or C(S)NH2;
R4, R5 and R6 are independently hydrogen, lower alkyl, aryl, aryl (lower alkyl), lower alkenyl, or lower alkynyl, wherein R4, R5 and R6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group;
R7 is R6, COOR8, or C(O)R8;
R8 is hydrogen or lower alkyl, or aryl (lower alkyl), and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group;
A and Q are independently O or S;
M is an alkylene chain containing up to 6 carbon atoms or a chemical bond;
n is 1-4; and
a is 1-3;
or a pharmaceutically acceptable salt thereof.
The present inventor has found that these peptides in U.S. Pat. Nos. 5,378,729 and 5,773,475, are useful for treating pain, including neuropathic pain, and headaches, including migraines and bipolar disorders. Moreover, these compounds are not addictive and do not exhibit the side effects of the commercially available drugs described hereinabove.